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Hassan A Al Saleh, Sandor Haas-Neill, Ali Al-Hashimi, Anil Kapoor, Bobby Shayegan, Richard C Austin, Khalid Al-Nedawi
BACKGROUND: Prostate cancer (PC) patients in advanced stages of the disease have high risk of blood coagulation complications. The procoagulant molecule Tissue factor (TF), and the fibrinolysis inhibitor plasminogen activator inhibitor-1 PAI-1 play important role in this complication. Extracellular vesicles (EV) shed from cancer cells may contribute to the regulation of TF and PAI-1. The procoagulant activity of EV can be associated with the oncogenic and metastatic characteristics of their cells...
May 15, 2018: Prostate
Soozana Puvanenthiran, Sharadah Essapen, Ben Haagsma, Izhar Bagwan, Margaret Green, Said Abdullah Khelwatty, Alan Seddon, Helmout Modjtahedi
EGFR and HER-2 are important targets but none of the monoclonal antibodies or small molecule tyrosine kinase inhibitors specific for the HER members has been approved for the treatment of patients with ovarian cancers. In some studies, co-expression of other growth factor receptors has been associated with resistance to therapy with the HER inhibitors. The aim of the present study was to determine the relative expression, cellular location, and prognostic significance of HER-family members, the EGFR mutant (EGFRvIII) c-MET, IGF-1R and the cancer stem cell biomarker CD44 in 60 patients with FIGO stage III and IV ovarian cancer...
April 13, 2018: Oncotarget
Corina N A M van den Heuvel, Arvid I Das, Tessa de Bitter, Femke Simmer, Thomas Wurdinger, Miguel Angel Molina-Vila, William P J Leenders
Oncogenic membrane receptor tyrosine kinases such as MET and EGFR, or auto-active variants thereof, are important targets for cancer precision therapy. Targeted inhibition of these oncogenic receptors however invariably leads to resistance, resulting from acquisition of resistance-inducing mutations or from selective outgrowth of a priori resistant tumour cells. Most applied molecular protocols cannot distinguish between intracellular and intercellular heterogeneity of oncogene (variant) expression, which may lead to misinterpretation of the molecular make-up of a cancer and suboptimal application of targeted therapies...
May 4, 2018: Scientific Reports
Alison Roos, Harshil D Dhruv, Sen Peng, Landon J Inge, Serdar Tuncali, Michael Pineda, Nghia Millard, Zachary Mayo, Jennifer M Eschbacher, Joseph C Loftus, Jeffrey A Winkles, Nhan L Tran
Glioblastoma multiforme (GBM) is the most common brain malignancies in adults. Most GBM patients succumb to the disease less than one year post-diagnosis due to the highly invasive nature of the tumor, which prevents complete surgical resection and gives rise to tumor recurrence. The invasive phenotype also confers radio- and chemo-resistant properties to the tumor cells; therefore, there is a critical need to develop new therapeutics that target drivers of GBM invasion. Amplification of EGFR is observed in over 50% of GBM tumors, of which half concurrently overexpress the variant EGFRvIII, and expression of both receptors confers a worse prognosis...
May 3, 2018: Molecular Cancer Research: MCR
Yiting Zhang, Jianhua Sun, Minjia Tan, Yongzhen Liu, Qian Li, Hua Jiang, Huamao Wang, Zonghai Li, Wei Wan, Hualiang Jiang, Henglei Lu, Bingshun Wang, Jin Ren, Likun Gong
CH12 is a novel humanized monoclonal antibody against epidermal growth factor receptor variant III (EGFRvIII) for cancer treatment. Unfortunately, in pre-clinical safety evaluation studies, acute thrombocytopenia was observed after administration of CH12 in cynomolgus monkeys, but not rats. More importantly, in vitro experiments found that CH12 can bind and activate platelets in cynomolgus monkey, but not human peripheral blood samples. Cynomolgus monkey-specific thrombocytopenia has been reported previously; however, the underlying mechanism remains unclear...
April 7, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Ivana De Pascalis, Liliana Morgante, Simone Pacioni, Quintino Giorgio D'Alessandris, Stefano Giannetti, Maurizio Martini, Lucia Ricci-Vitiani, Matteo Malinverno, Elisabetta Dejana, Luigi M Larocca, Roberto Pallini
We hypothesized that in glioblastoma recurring after radiotherapy, a condition whereby the brain endothelium undergoes radiation-induced senescence, tumor cells with endothelial phenotype may be relevant for tumor neovascularization. Matched glioblastoma samples obtained at primary surgery and at surgery for tumor recurrence after radiotherapy, all expressing epidermal growth factor receptor variant III (EGFRvIII), were assessed by a technique that combines fluorescent in situ hybridization (FISH) for the EGFR/CEP7 chromosomal probe with immunostaining for endothelial cells (CD31) and activated pericytes (α Smooth Muscle Actin)...
April 30, 2018: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
Jianying Niu, Changhong Li, Yinji Jin, Rui Xing, Lin Sun, Ruohan Yu, Leilei Jian, Xiangyuan Liu, Lin Yang
Epidermal growth factor receptor (EGFR) signaling has been reported to play a vital role in the pathogenesis of rheumatoid arthritis (RA). In current study, we sought to observe whether the active immunization induced by the mimotope could recognize EGFR, inhibit their signaling and disrupt the pathogenic behavior of fibroblast-like synoviocytes (FLS) from RA patients. We prepared a linked EGFR mimotope and performed series of experiments to detect whether the mimotope could induce the desired immune responses...
April 27, 2018: Immunology Letters
Patrick C Gedeon, Teilo H Schaller, Satish K Chitneni, Bryan D Choi, Chien-Tsun Kuan, Carter M Suryadevara, David J Snyder, Robert J Schmittling, Scott E Szafranski, Xiuyu Cui, Patrick Healy, James E Herndon, Roger E McLendon, Stephen T Keir, Gary E Archer, Elizabeth Reap, Luis Sanchez-Perez, Darell D Bigner, John H Sampson
PURPOSE: Conventional therapy for malignant glioma (MG) fails to specifically target tumor cells. In contrast, substantial evidence indicates that if appropriately redirected, T cells can precisely eradicate tumors. Here we report the rational development of a fully-human bispecific antibody (hEGFRvIII-CD3 bi-scFv) that redirects human T cells to lyse MG expressing a tumor-specific mutation of the epidermal growth factor receptor (EGFRvIII). EXPERIMENTAL DESIGN: We generated a panel of bispecific single-chain variable-fragments and optimized design through successive rounds of screening and refinement...
April 27, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Feng Li, Tengfei Zhang, Ling Cao, Yi Zhang
Cancer immunotherapy, a new weapon against cancers by harnessing the patient's own immune system, potentiates an extended remission and possibly a cure for cancer. T cells genetically engineered with chimeric antigen receptor (CAR) vectors can specifically target the surface antigen of cancer cells and kill them in an MHC-independent manner. CD19 is extensively expressed on cancerous cells in B cell malignancies. To target this antigen, CAR T cells have gained great success in treating patients with B cell leukemia and lymphoma...
April 19, 2018: Current Stem Cell Research & Therapy
Sylvia C Kurz, Patrick Y Wen
PURPOSE OF REVIEW: More effective therapies for glioblastoma are urgently needed. Immunotherapeutic strategies appear particularly promising and are therefore intensively studied. This article reviews the current understanding of the immunosuppressive glioblastoma microenvironment, discusses the rationale behind various immunotherapies, and outlines the findings of several recently published clinical studies. RECENT FINDINGS: The results of CheckMate-143 indicated that nivolumab is not superior to bevacizumab in patients with recurrent glioblastoma...
April 18, 2018: Current Treatment Options in Neurology
Tomoyuki Koga, Bin Li, Javier M Figueroa, Bing Ren, Clark C Chen, Bob S Carter, Frank B Furnari
Background: Epidermal growth factor receptor (EGFR) variant III (vIII) is the most common oncogenic rearrangement in glioblastoma (GBM) generated by deletion of exons two to seven of EGFR. The proximal breakpoints occur in variable positions within the 123-kb intron one, presenting significant challenges in terms of PCR-based mapping. Molecular mechanisms underlying these deletions remain unclear. Methods: We determined the presence of EGFRvIII and its breakpoints for 29 GBM samples using quantitative polymerase chain reaction (qPCR), arrayed PCR mapping, Sanger sequencing, and whole genome sequencing (WGS)...
April 12, 2018: Neuro-oncology
So Yeon Kim, Jeong-Yub Kim, Woon-Seob Shin, Seok Joon Lee, Sung-Gil Chi, Ji-Yun Lee, Myung-Jin Park
Cancer stem cells, a small subpopulation of cells with stem cell-like characteristics found within most solid tumors, are widely reported to be responsible for the malignancy of aggressive cancer cells, and targeting these cells presents a sound therapeutic strategy for reducing the risk of tumor relapse. In the present study, we examined the effects of an extract of Saccharina japonica (ESJ) on glioblastoma stem cells (GSCs). Saccharina japonica is a member of the Phaeophyceae (brown algae) family, which displays biological activities, including antitumor effects...
March 14, 2018: Journal of Medicinal Food
Hamed Akbari, Spyridon Bakas, Jared M Pisapia, MacLean P Nasrallah, Martin Rozycki, Maria Martinez-Lage, Jennifer J D Morrissette, Nadia Dahmane, Donald M O'Rourke, Christos Davatzikos
Background: Epidermal growth factor receptor variant III (EGFRvIII) is a driver mutation and potential therapeutic target in glioblastoma. Non-invasive in vivo EGFRvIII determination, using clinically acquired multiparametric MRI sequences, could assist in assessing spatial heterogeneity related to EGFRvIII, currently not captured via single-specimen analyses. We hypothesize that integration of subtle, yet distinctive, quantitative imaging/radiomic patterns using machine learning may lead to non-invasively determining molecular characteristics, and particularly the EGFRvIII mutation...
March 30, 2018: Neuro-oncology
Thomas Nittoli, Marcus P Kelly, Frank Delfino, John Rudge, Arthur Kunz, Thomas Markotan, Jan Spink, Zhaoyuan Chen, Jing Shan, Elizabeth Navarro, Michele Tait, Kathleen Provoncha, Jason Giurleo, Feng Zhao, Xiaobo Jiang, Donna Hylton, Sosina Makonnen, Carlos Hickey, Jessica R Kirshner, Gavin Thurston, Nicholas Papadopoulos
Natural products have been used for many medicinal purposes for centuries. Antibody drug conjugates (ADCs) have utilized this rich source of small molecule therapeutics to produce several clinically useful treatments. ADCs based on the natural product maytansine have been successful clinically. The authors further the utility of the anti-cancer natural product maytansine by developing efficacious payloads and linker-payloads for conjugating to antibodies. The success of our approach was realized in the EGFRvIII targeting ADC EGFRvIII-16...
February 21, 2018: Bioorganic & Medicinal Chemistry
Michael Platten, Lukas Bunse, Dennis Riehl, Theresa Bunse, Katharina Ochs, Wolfgang Wick
PURPOSE OF REVIEW: To discuss the current state of glioma vaccine development and highlight the challenges associated with clinical implementation of these approaches. RECENT FINDINGS: Vaccination strategies against gliomas have matured considerably during the past years, although proof-of efficacy from controlled clinical trials is still lacking. Advances in antigen discovery, including the definition of neoepitopes including epidermal growth factor receptor variant III (EGFRvIII), isocitrate dehydrogenase (IDH)1R132H and Histone (H)3...
March 28, 2018: Current Treatment Options in Neurology
Wen Xu, Fei Song, Biao Wang, Kesang Li, Mi Tian, Min Yu, Xiaorong Pan, Bizhi Shi, Jianwen Liu, Jianren Gu, Zonghai Li, Hua Jiang
BACKGROUND/AIMS: Epidermal growth factor receptor variant III (EGFRvIII), the most frequent EGFR variant, is constitutively activated without binding to EGF and is correlated with a poor prognosis. CH12, a human-mouse chimeric monoclonal antibody, has been developed in our laboratory and selectively binds to overexpressed EGFR and EGFRvIII. A previous study had reported that EGFR could influence autophagic activity, and autophagy is closely related to tumor development and the response to drug therapy...
March 21, 2018: Cellular Physiology and Biochemistry
Raelene Endersby, Jacqueline Whitehouse, Hilary Hii, Sameer A Greenall, Terrance G Johns, Nicholas G Gottardo
Glioblastoma in adults, and medulloblastoma and pineoblastoma that mainly affect children, are aggressive brain tumors. The survival for patients with glioblastoma remains dismal. While the cure rate for medulloblastoma exceeds 70%, this figure has stagnated over the past few decades and survivors still contend with significant long-term debilitating side effects. The prognosis for pineoblastoma is age-dependent, with little chance of a cure for children younger than three years. More effective molecularly targeted strategies are urgently required to treat these cancers...
March 22, 2018: Neoplasia: An International Journal for Oncology Research
Saima Rathore, Hamed Akbari, Martin Rozycki, Kalil G Abdullah, MacLean P Nasrallah, Zev A Binder, Ramana V Davuluri, Robert A Lustig, Nadia Dahmane, Michel Bilello, Donald M O'Rourke, Christos Davatzikos
The remarkable heterogeneity of glioblastoma, across patients and over time, is one of the main challenges in precision diagnostics and treatment planning. Non-invasive in vivo characterization of this heterogeneity using imaging could assist in understanding disease subtypes, as well as in risk-stratification and treatment planning of glioblastoma. The current study leveraged advanced imaging analytics and radiomic approaches applied to multi-parametric MRI of de novo glioblastoma patients (n = 208 discovery, n = 53 replication), and discovered three distinct and reproducible imaging subtypes of glioblastoma, with differential clinical outcome and underlying molecular characteristics, including isocitrate dehydrogenase-1 (IDH1), O6 -methylguanine-DNA methyltransferase, epidermal growth factor receptor variant III (EGFRvIII), and transcriptomic subtype composition...
March 23, 2018: Scientific Reports
Stephen T Keir, Vidyalakshmi Chandramohan, Carlee D Hemphill, Michael M Grandal, Maria Carlsen Melander, Mikkel W Pedersen, Ivan D Horak, Michael Kragh, Annick Desjardins, Henry S Friedman, Darell D Bigner
BACKGROUND: Sym004 is a mixture of two monoclonal antibodies (mAbs), futuximab and modotuximab, targeting non-overlapping epitopes on the epidermal growth factor receptor (EGFR). Previous studies have shown that Sym004 is more efficient at inducing internalization and degradation of EGFR than individual components, which translates into superior cancer cell inhibition. We investigated whether Sym004 induces removal of EGFRvIII and if this removal translates into tumor growth inhibition in hard-to-treat glioblastomas (GBMs) harboring the mutated, constitutively active EGFR variant III (EGFRvIII)...
March 21, 2018: Journal of Neuro-oncology
Yiguang Lin, Junhu Zhou, Jianglong Xu, Kai Zhao, Xiaomin Liu, Guokai Wang, Zhiyuan Zhang, Youlin Ge, Yongqing Zong, Desheng Xu, Yanli Tan, Chuan Fang, Chunsheng Kang
Glioblastoma multiforme (GBM) is a highly malignant and notably aggressive primary tumour. Variant III of the epidermal growth factor receptor (EGFRvIII) is one of the most common types of variants in GBM, and serves an important role in tumour invasion, proliferation and treatment resistance. In the present study, statistical analyses were performed on data from 57 patients with GBM, and polymerase chain reaction detection was conducted on the tumour tissues from 32 of these patients. The results indicated that the EGFRvIII mutation was significantly associated with tumour malignancy...
April 2018: Oncology Letters
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